High BRAF variant allele frequencies are associated with distinct pathological features and responsiveness to target therapy in melanoma patients

Abstract

Background: BRAF mutant melanoma patients are commonly treated with anti-BRAF therapeutic strategies. However, many factors, including the percentage of BRAF-mutated cells, may contribute to the great variability in patient outcomes.Patients and methods: The BRAF variant allele frequency (VAF; defined as the percentage of mutated alleles) of primary and secondary melanoma lesions, obtained from 327 patients with different disease stages, was assessed by pyrosequencing. The BRAF mutation rate and VAF were then correlated with melanoma pathological features and patients' clinical characteristics. KaplaneMeier curves were used to study the correlations between BRAF VAF, overall survival (OS), and progression-free survival (PFS) in a subset of 62 patients treated by anti-BRAF/anti-MEK therapy after metastatic progression. Results: A highly heterogeneous BRAF VAF was identified (3%-90%). Besides being correlated with age, a higher BRAF VAF level was related to moderate lymphocytic infiltration (P ¼ 0.017), to melanoma thickness according to Clark levels, (level V versus III, P ¼ 0.004; level V versus IV, P ¼ 0.04), to lymph node metastases rather than cutaneous (P ¼ 0.04) or visceral (P ¼ 0.03) secondary lesions. In particular, a BRAF VAF >25% was significantly associated with a favorable outcome in patients treated with the combination of anti-BRAF/anti-MEK drug (OS P ¼ 0.04; PFS P ¼ 0.019), retaining a significant value as an independent factor for the OS and the PFS in the multivariate analysis (P ¼ 0.014 and P ¼ 0.003, respectively). Conclusion: These results definitively support the role of the BRAF VAF as a potential prognostic and predictive biomarker in melanoma patients in the context of BRAF inhibition.

Prevalence and breakdown of non-small cell lung cancer BRAF driver mutations in a large UK cohort

“…However, the V600E incidence rate described in this cohort (69/5384, 1.28 %) was slightly lower, but broadly in line with other published data, in keeping with which V600E was the single most commonly detected mutation [8]. BRAF mutation VAF was highly heterogeneous across all three mutation classes, which is broadly in line with findings in patients with melanoma [9], though the significance of the lower mean VAF in Class I mutations is uncertain.…”

Genetic Alterations Predict Long-Term Survival in Ductal Adenocarcinoma of the Pancreatic Head

“…These different median allele frequency rates of pathogenic KRAS mutations between short-and long-term PDAC survivors might be explained by the role of KRAS mutations in inducing tumor progression, with tumors showing higher allele frequency rates for pathogenic KRAS mutations, i.e., tumors harboring a higher proportion of KRAS-mutated subclones, showing a faster tumor progression, hence its link to early disease recurrence in our study. The impact of the allele frequencies of pathogenic mutations on patient outcome has already been evaluated in other solid malignancies, e.g., in malignant melanoma [43].…”

BRAFV600E Mutant Allele Frequency (MAF) Influences Melanoma Clinicopathologic Characteristics

“…In recent years, controversial results have been obtained by studies which related the BRAF V600E MAF of melanoma tumors with clinicopathological and prognostic characteristics as well as the melanoma response, in order to target therapies [15,[23][24][25][26]. All these studies analyzed the MAF value of one specific region for each tumor, so we wanted to know whether the variation degree of BRAF V600E MAF within different regions of the same tumor could influence these characteristics.…”

“…Besides the usefulness of the BRAF V600E driver mutation as a therapeutic target, a recent study has suggested that the mutational load of BRAF V600E is a possible prognostic biomarker [15], expanding the classical histopathological prognostic criteria such as ulceration, Breslow, Clark or mitotic indexes [1,[16][17][18][19][20][21][22]. Moreover, some studies in recent years have attempted to relate the mutational load to the response in order to target therapies, but controversial results have been obtained [23][24][25][26].…”